The present invention relates to a solidified drug supply for generating inhalable drug particles with the aid of a metering device comprising removal means.
Drug supplies of this type are known from WO 93/24165 and are used in aerosol generators having a metering device which includes removal means, for example, in the form of a driven face cutter, for removing drug particles from the drug supply and generating an aerosol which is released for oral or nasal inhalation at the instant when it is generated.
From DE 40 27 390 A1 there is known an inhalation device wherein a brush is used to remove dust-like particles from a tablet wherein the geometrical form of the tablet may vary.
EP 040702882 also describes an aerosol generator having a pressed body of an inhalable drug. The pressure suggested for pressing the drug supply is a so-called lightly densified pressure range between 1.times.10.sup.4 to 15.times.10.sup.4 N/m.sup.2 as well as a strongly densified pressure range between 30.times.10.sup.4 and 150.times.10.sup.4 N/m.sup.2. However, even this higher pressure range is set to such a low value that the manageable structure can only exist because the drug supply is pressed into a cylindrical container and is held together by that container. Since the drug supply is not compacted very densely, a homogeneous pressure distribution in the bulk of the drug material is not achieved because of the internal friction effects in the bulk and because of the friction between the drug supply and the container wall. As a result, drug supplies of this type exhibit density gradients of more than 40% which have a negative effect on the metering accuracy (see also: B. Chariton and J. M. Newton, "Application of Gamma Ray Attenuation to the Determination of Density Distribution within Compacted Powders", Powder Technology 41 (1985), 123 to 134).
Since according to a publication of the applicant of EP 0 407 028 A2, the densities of the drug supply are about 0.8 to 0.9 g/cm.sup.-3, the volume density for the densified drug supply is calculated to be about 50% of the theoretical density. Accordingly, such a highly porous drug supply is not only very porous and inhomogeneous, but is, as a result of the large open porosity, also subjected to agglomeration and to aging caused by the atmospheric factors, such as humidity and the like.
A solidified drug supply is known from PCT/EP 93/00158, wherein the significance of structural and chemical homogeneity of the solidified drug supply for the metering accuracy pointed out. Therein, isostatic pressing is proposed for obtaining a proper structure; this pressing (molding) method is known from powder metallurgy when flexible forms are employed. Herein, a batch of powder disposed, for instance, inside a rubber form, is densified all around and therefore isostatically from the outside with the help of a pressure liquid. Also proposed in this publication are other forming methods aside from isostatic pressing, for example, injection molding of plastified materials.
Further investigations on solidified drug supplies have shown that the quality requirements with respect to structure are much higher than have been assumed previously. It has been found that during removal by a metering device comprising a removal means, such as known from WO 93/24165, potential variations in density can have a significant effect on the generated amount of aerosol.
It was also observed that isostatically pressed drug supplies initially exhibit inexplicable dose variations at the removal end face, which could not be explained by density or material inhomogeneities measured in the bulk. A more accurate investigation of these occurrences has demonstrated that defects in material, such as texturing and micro-fissures, occur in these marginal regions whereby larger sections of material may chip off during removal, resulting in dosage variations.
It now appears that such defects in material are the result of the isostatic pressing process. Strictly speaking, an ideal isostatic pressure transmission to the powder material occurs only in forms of spherical or nearly spherical geometry. If, however, the shape of the form deviates from the isometric form which is, for example, the case for ring-shaped removal members for inhalation purposes, then the pressure transmission is no longer completely isostatic, but is directional. If, for example, such ring-shaped tablet for an inhalator is isostatically pressed, then radial and axial forces are superposed in the region of the end faces, wherein these forces cause texturing in the critical regions of the end faces, in particular, since a form with this shape exhibits a different stiffness with respect to the hydrostatic pressure and consequently a different deformability when the pressure is building up. This causes an initial densification phase in radial direction and a subsequent post-densification of the already pre-solidified powder material in axial direction which causes the aforementioned textures and micro-fissures in the structure of the ring-shaped tablet. For the known applications of isostatic molding (pressing) in the field of powder metallurgy and ceramics, such developments usually are not important, since the resulting structural defects are annealed during the subsequent sintering process without leaving any blemishes. This possibility however, does not exist with a drug supply which is used without such post-treatment.
It has been found that the above-mentioned friction effects inside a bulk powder material also occur when a drug supply is isostatically pressed, however, not to such extent as with unidirectional pressing methods. Even for an isostatic pressing operation, the pressure loss inside the bulk powder increases with the thickness of the form in the direction facing the pressing force. Consequently, density gradients within the cylinder walls in radial and axial direction occur also during isostatic pressing of a ring tablet, resulting in completely formed zone of equal densities or textures, respectively, in the region of the end face.